CHAPTER 2 Hepatitis C---viral hepatitis A,B,C,D, and E.
After hepatitis A and B were identified the world’s blood supply was safer, but not “safe”. At least one more virus, an entity called non A non B, was still infecting man. (A British researcher named Evie Tabor, had sort-of “proved” the problem was caused by a virus. Her team inoculated two chimpanzees with serum from a patient with a chronic non-A, non-B hepatitis. The patient’s blood had previously transmitted the disease to a nurse following accidental needle-stick.
After the monkeys were
infused with the man’s blood their liver enzymes rose and a biopsy of their
livers showed evidence of hepatitis.
Tests for hepatitis A and B were negative. ) (2)
In 1982 a research team led by Michael Houghton, working at California pharmaceutical research house Chiron, began looking for the virus. Their quest “ended up taking 7 years, a lot of false leads, a lot of frustration.” In the end, using blood from an infected patient and blood from an infected chimpanzee his team identified a small piece of nucleic acid--- a 100 nucleoside base pair –that was eventually identified as all or part of the hepatitis C virus. It allowed him to identify the entire virus and develop tests that would allow doctors to screen blood before it was transfused and to diagnose people who had the disease.(1)
Ten years later Houghton became a Professor of Virology at the University of Alberta in Canada and in 2013 was offered the prestigious Canada Gairdner International Award. He refused to accept it unless two of his co-workers were included. The prize committee turned him down and gave the honor to someone else.
In 2020 he
was offered the Nobel Prize and this time he accepted. When he was interviewed before the ceremony
he talked about growing up in England and recalled being inspired by Sunday
morning BBC programs that told the story of Watson and Crick and the “elucidation” of the structure of DNA. He was a child and would get up early just to
watch. In high school he was interested
in biology, and at one point he spent a week in the local library thinking
seriously about what career he wanted. When he got to ‘M’ – microbiology – he
read about Louis Pasteur’s work and his life story and thought, this is what I
want to do. He attended a traditional high school in the UK where he was told
what to do, and often what to think and in college was released into a really
open community at the University of East Anglia. As a student he drank beer,
participated in sports and --“I wouldn’t say I went off the rails but my work
suffered!” He later earned a PhD in
biochemistry, worked for Searle, and later decided to try to identify the
hepatitis C virus. He liked the idea of
looking at disease and then working with other scientists to figure out ways to
prevent that disease. His search took
his group a lot of effort and the best part of seven years. There was a fair bit of pressure. His work was done in a biotech company where
the investors are always asking when, when, when, where’s the virus? (3)
Discovering the marker for hepatitis C was the medical equivalent of striking oil; bringing in a gusher. 1.8 % of the people in this country were antibody positive, which means at some point in their lives they were infected with the virus and they had developed antibodies. 75% of those who had been infected still were. Most people with chronic infections have millions of viruses in each drop of their blood. Some had liver inflammation, others cirrhosis. Our blood supply wasn’t pure. Transfusions and dialysis units spread the disease.
15% of individuals who are infected as adults develop a self limited form of the disease. Of the remaining 85%, a third have recurrent or chronic flares from the get go. They usually died or were transplanted within 20 years. A third died of some other cause long before they developed liver problems; and a third developed slowly progressive liver inflammation in their thirties, forties or fifties.
Interferons could often, team up with the body to destroy the C virus. I’d heard about these proteins in medical school. First discovered in 1957 they are a strain of naturally occurring peptides that play an important role in protecting cells from viruses.
When we gave people with Hepatitis C three interferon injections a week for a year, we cured a few people, but we usually failed. The drug was expensive and had lots of side effects. Over the next decade we combined a once a week injection with a second antiviral. As our success rate improved, the benefits of treatment seemed to exceed the risk, and we geared up big time. Our approach became more aggressive, more search and destroy. (In my experience most people over 60 who had “inactive” hepatitis C didn’t want to be treated, while those in their 40s wanted to “go for it.”)
Unlike hepatitis B we weren’t suppressing a virus, we were trying to cure it, make it go away permanently. Treatment took a year to a year and a half. There were weekly injections, pills twice a day, blood tests, and frequent communication with a doctor or nurse. Interferon suppressed the bone marrow, exhausted people and sometimes triggered depression. Ribavirin, the other drug we used, made people anemic. The price of the standard anti hepatitis C drugs was $600 a week or close to $30,000 for the year long course of therapy. The cost of testing, medical visits, and lost productivity or work days was extra.
There were failures and the drugs sometimes left people with residual harm.(4)
I
recall telling a young man who was being treated: “If you get interferon on a
Friday, you will be sick on Saturday and Sunday, but will probably be well
enough to go to work Monday. Would you like to be treated that way?”
“And ruin my weekend?” He shook his head. “I don’t think so.”
My colleagues and I treated hundreds of people using this regimen. The process was emotionally trying, but the people who desperately wanted to be cured endured the weekly draining days. In a significant minority, the treatment didn’t eradicate their disease, and for many that was heartbreaking.
Then a small company started by Raymond Schinazi developed a cure. Schinazi, the doctor who oversaw the development of the therapeutic drug, was a Jew, born in Alexandria, Egypt. When Israel and Egypt fought a war in 1956, Egyptian Jews became personae non grata. His family moved to Italy, and he later studied at Bath in the U.K. “As a student he lived on 100 English pounds a month, worked as a parking attendant to help pay his way, and didn’t have real money in his pocket until he won 3000 pounds in the Spanish lottery.” After receiving his British degree, he did his post doc work in Yale and spent three years making “chemicals similar to Nucleosides.” Described as a “bear-sized man who speaks bluntly, negotiates fiercely, and favors splashy, multicolored shirts,” Dr. Schinazi enjoyed the science but not the weather at Yale.
“We had two really cold winters in a row in New Haven, with tons and tons of snow.”
When the world learned HIV was caused by a virus, Schinazi was a professor of pediatrics at the VA hospital in Atlanta. As he explained (in interviews), he “couldn’t just sit around and do nothing.” He wanted to attack the virus with nucleoside analogues and the VA resisted. (7)
(Nucleosides are chemical precursors to the nucleotides that make up DNA and RNA. When viruses copy themselves, they string together nucleotides. Chemical modifications can create defective analogs of these building blocks. Viruses incorporate them into a growing chain of nucleotides but usually cannot add new links, gumming up production of genetic material and aborting viral replication.
“Nucleotide analogs typically make lousy drugs: The molecules are highly charged and have difficulty entering cells. Not so for nucleoside analogs, which cells convert into nucleotides. But they can cause serious toxicities if they get into human DNA or RNA.
At the time Schinazi joined Prusoff’s lab in 1976, many drug developers shunned them.
In 1989, Shinazi learned of a potential drug developed by a Canadian biotech, BioChem International. The drug, a synthetic nucleoside, contained an equal mixture of mirror-image “enantiomers”—left- and right-hand versions of the same molecule. Because enantiomers can have different powers and toxicities, Schinazi saw an opportunity. He enlisted Dennis Liotta, a chemist at Emory, to see if they could sort out the enantiomers. “I was a pretty good chemist and Ray had a background in virology,” Liotta says. “It turned out to be an excellent combination.”)
Eventually, Schinazi helped develop two of the more significant anti-HIV drugs and made sure Emory University profited from the sale of the medications.
Encouraged by his success, Schinazi wanted to try to develop an anti–hepatitis C drug. The NIH, allegedly, turned down his application for the project. Schinazi and a partner got venture funding and founded Pharmasset. One of their company chemists, Michael Sofia, developed sofosbuvir, a drug that, with a little help, almost always cured hepatitis C in 12 weeks “
Pharmasset planned to sell the drug at a total cost per treatment of around $30,000, but in 2011 Gilead bought Pharmasset for $11 billion. Schinazi received $440 million and went on to do further research. Gilead now had to charge a lot for the medication. The original list U.S. price for the company’s two drug combination, Harvoni, was $94,000.
During an interview with journalist Jon Cohen, Shinazi was asked about “Sofosbuvir’s price tag of $1000 per pill.” Shinazi pointed out that Gilead decides on the price, and he called it “obscene” but not unreasonable. “Is it fair to pay $3 for a bottle of water when you’re thirsty? This is something that cures you from a disease.”
Once
Gilead owned the anti-virals, it spent $60 to $80 million
on TV ads. Actors faced the camera and said they were “ready” to be cured. The
company needed to sell a lot before they faced competition, before the
medication became one of several low-cost commodities. In 2014, Gilead’s drug
combination, Harvoni (ledipasvir/sofosbuvir), created revenues of more than $10
billion. (5)
In 2014, Schinazi, working with the Egyptian government and Gilead Sciences, agreed to provide Egypt with the drug Sofosbuvir (Sovaldi) for about US$1,000, which is only one percent of its market price. Also working with Pharco, an Egyptian Pharmaceutical company Sovaldi is now available for less than US$120 per cure. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664204/
“WHO recommends therapy with pan-genotypic direct-acting antivirals (DAAs) for all adults, adolescents and children down to 3 years of age with chronic hepatitis C infection. The short-course oral, curative direct acting antiviral treatment regimens has few if any side-effects. The drugs can cure most persons with HCV infection, and treatment duration is short (usually 12 to 24 weeks), depending on the absence or presence of cirrhosis.
“In 2022, WHO included new recommendations for treatment of adolescents and children using the same pangenotypic treatments used for adults.
“These drugs remain quite expensive in many high- and upper-middle-income countries. However, prices have dropped dramatically in many countries (primarily low-income and lower-middle-income countries) due to the introduction of generic versions of these medicines. The most widely used and low-cost direct acting antiviral regimen is sofosbuvir and daclatasvir. In many low- and middle-income countries the curative treatment course is available for less than US$ 50.
“Access to HCV treatment is improving but remains limited. Of the 50 million people living with HCV infection globally in 2022, an estimated 36% people knew their diagnosis, and of those diagnosed with chronic HCV infection, around 20% (12.5 million) people had been treated with direct acting antivirals by the end of 2022.”
Globally, an estimated 50 million people have chronic hepatitis C virus infection, with about 1.0 million new infections occurring per year.
WHO estimated that in 2022, approximately 242 000 people
died from hepatitis C, mostly from cirrhosis and hepatocellular carcinoma
(primary liver cancer).
1. https://www.youtube.com/watch?v=Bc61-nzuZSo
2. https://pubmed.ncbi.nlm.nih.gov/10604241/
3.
https://www.youtube.com/?bp=wgUCEAE%3D
https://pubmed.ncbi.nlm.nih.gov/19781804/
5. https://joncohen.org/2015/05/08/king-of-the-pills/
https://www.youtube.com/watch?v=dPt62_MHW10
https://www.youtube.com/watch?v=-rFm-QAHm_E
7.
From King of the pills-- By Jon Cohen
https://www.science.org/doi/full/10.1126/science.348.6235.622
https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
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